Abstract The negative health consequences of cigarette smoking (CS) are indisputable: extensive heart and lung damage and significant risk for multiple types of cancer. Similarly, the addictive properties of CS are also well- documented. Epidemiological studies have repeatedly shown that cigarette addiction is highly comorbid with alcohol and other substance use disorders (AUD, SUD). Discussions of these data typically center around concern for the serious peripheral health consequences of smoking and/or risk for relapse for AUD/SUD. While these are worthy topics of inquiry, the current state of the literature has failed to address several critical points: first, while smoking rates are decreasing in the general U.S. population, they remain high in AUD/SUD. Second, while we know that the toxic compounds in combustible tobacco products are highly likely to induce brain damage, we do not yet have an understanding of putative dose-response functions of smoking history and current CS status on markers of neural damage. Third, it is not known how lifetime CS exposure interacts with other addictions at the level of brain structure and biochemistry to produce behavior: this could be key for discovering how the cycle of comorbid addictions is perpetuated, and thus is crucial for advancing treatment and predicting outcomes. Recently, a wealth of neuroimaging studies have emerged that have examined brain structure in chronic smokers. However, the majority of these studies looked at single outcome variables, only considered cigarette addiction, and did not design the studies from a perspective of a brain damage hypothesis. What are missing is information derived from comprehensive, multi-modal studies that attempt to understand the caustic effects of CS on the brain, and data that inform us of how CS exposure may compound effects of and complicate outcomes in CS comorbid with AUD/SUD. Lack of such knowledge is an important, clinically relevant problem, as it prevents us from developing targeted, mechanism-driven therapies designed to promote both smoking cessation and alcohol/drug abstinence, and to mitigate or repair brain damage from CS. We propose to address this critical knowledge gap by applying state-of-the art neuroimaging technologies to determine how the lifetime dose response function of CS exerts negative consequences on the brain in AUD. We will conduct parallel studies at the Indiana University School of Medicine and Stanford. Both sites will recruit the following samples: never-smoking controls, currently-smoking controls, never-smoking AUD, former-smoking AUD, and currently-smoking AUD. All AUD subjects will be nontreatment-seeking and active drinkers. We will test the effects of lifetime CS exposure on brain metabolites (Aim 1), white matter tract integrity (Aim 2), and brain network function (Aim 3). Exploratory Aim 4 will develop a predictively valid model of the relative contributions of CS-mediated brain damage on neurocognition and drinking behaviors. The dual-site design maximizes the power of the study by sampling two geographically distinct populations, and has a built-in replication component that is crucial, but often not realized in human neuroimaging studies.